Biopolym. Cell. 2014; 30(4):260-272.
Transcription factor CTCF and mammalian genome organization
1Kotova E. S., 1Akopov S. B., 1Sverdlov E. D., 1Nikolaev L. G.
  1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS
    16/10, Miklukho-Maklaya, Moscow, Russian Federation, 117997


The CTCF transcription factor is thought to be one of the main participants in various gene regulatory networks including transcription activation and repression, formation of independently functioning chromatin domains, regulation of imprinting etc. Sequencing of human and other genomes opened up a possibility to ascertain the genomic distribution of CTCF binding sites and to identify CTCF-dependent cis-regulatory elements, including insulators. In the review, we summarized recent data on CTCF functioning within a framework of the chromatin loop domain hypothesis of large-scale regulation of the genome activity. Its fundamental properties allow CTCF to serve as a transcription factor, an insulator protein and a dispersed genome-wide demarcation tool able to recruit various factors that emerge in response to diverse external and internal signals, and thus to exert its signal-specific function(s).
Keywords: ranscription factor CTCF, chromatin, transcription regulation


[1] Holwerda SJ, de Laat W. CTCF: the protein, the binding partners, the binding sites and their chromatin loops. Philos Trans R Soc Lond B Biol Sci. 2013;368(1620):20120369.
[2] Nikolaev LG, Akopov SB, Didych DA, Sverdlov ED. Vertebrate Protein CTCF and its Multiple Roles in a Large-Scale Regulation of Genome Activity. Curr Genomics. 2009;10(5):294-302.
[3] Phillips JE, Corces VG. CTCF: master weaver of the genome. Cell. 2009;137(7):1194-211.
[4] Lobanenkov VV, Gudvin GG. CCCTC-binding protein: a new nuclear protein factor which interaction with 5'-flanking sequence of chicken c-myc oncogene correlates with repression of the gene. Dokl Akad Nauk SSSR. 1989;309(3):741-5.
[5] Lobanenkov VV, Nicolas RH, Adler VV, Paterson H, Klenova EM, Polotskaja AV, Goodwin GH. A novel sequence-specific DNA binding protein which interacts with three regularly spaced direct repeats of the CCCTC-motif in the 5'-flanking sequence of the chicken c-myc gene. Oncogene. 1990;5(12):1743-53.
[6] Baniahmad A, Steiner C, K?hne AC, Renkawitz R. Modular structure of a chicken lysozyme silencer: involvement of an unusual thyroid hormone receptor binding site. Cell. 1990;61(3):505-14.
[7] Burcin M, Arnold R, Lutz M, Kaiser B, Runge D, Lottspeich F, Filippova GN, Lobanenkov VV, Renkawitz R. Negative protein 1, which is required for function of the chicken lysozyme gene silencer in conjunction with hormone receptors, is identical to the multivalent zinc finger repressor CTCF. Mol Cell Biol. 1997;17(3):1281-8.
[8] Bell AC, West AG, Felsenfeld G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell. 1999;98(3):387-96.
[9] Klenova EM, Nicolas RH, Paterson HF, Carne AF, Heath CM, Goodwin GH, Neiman PE, Lobanenkov VV. CTCF, a conserved nuclear factor required for optimal transcriptional activity of the chicken c-myc gene, is an 11-Zn-finger protein differentially expressed in multiple forms. Mol Cell Biol. 1993;13(12):7612-24.
[10] Robinett CC, O'Connor A, Dunaway M. The repeat organizer, a specialized insulator element within the intergenic spacer of the Xenopus rRNA genes. Mol Cell Biol. 1997;17(5):2866-75.
[11] Filippova GN, Fagerlie S, Klenova EM, Myers C, Dehner Y, Goodwin G, Neiman PE, Collins SJ, Lobanenkov VV. An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes. Mol Cell Biol. 1996;16(6):2802-13.
[12] Ohlsson R, Renkawitz R, Lobanenkov V. CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease. Trends Genet. 2001;17(9):520-7.
[13] Klenova EM, Chernukhin IV, El-Kady A, Lee RE, Pugacheva EM, Loukinov DI, Goodwin GH, Delgado D, Filippova GN, Le?n J, Morse HC 3rd, Neiman PE, Lobanenkov VV. Functional phosphorylation sites in the C-terminal region of the multivalent multifunctional transcriptional factor CTCF. Mol Cell Biol. 2001;21(6):2221-34.
[14] Klenova E, Ohlsson R. Poly(ADP-ribosyl)ation and epigenetics. Is CTCF PARt of the plot? Cell Cycle. 2005;4(1):96-101.
[15] Kitchen NS, Schoenherr CJ. Sumoylation modulates a domain in CTCF that activates transcription and decondenses chromatin. J Cell Biochem. 2010;111(3):665-75.
[16] MacPherson MJ, Beatty LG, Zhou W, Du M, Sadowski PD. The CTCF insulator protein is posttranslationally modified by SUMO. Mol Cell Biol. 2009;29(3):714-25.
[17] Wang J, Wang Y, Lu L. De-SUMOylation of CCCTC binding factor (CTCF) in hypoxic stress-induced human corneal epithelial cells. J Biol Chem. 2012;287(15):12469-79.
[18] Heger P, Marin B, Bartkuhn M, Schierenberg E, Wiehe T. The chromatin insulator CTCF and the emergence of metazoan diversity. Proc Natl Acad Sci U S A. 2012;109(43):17507-12.
[19] Heath H, Ribeiro de Almeida C, Sleutels F, Dingjan G, van de Nobelen S, Jonkers I, Ling KW, Gribnau J, Renkawitz R, Grosveld F, Hendriks RW, Galjart N. CTCF regulates cell cycle progression of alphabeta T cells in the thymus. EMBO J. 2008;27(21):2839-50.
[20] Splinter E, Heath H, Kooren J, Palstra RJ, Klous P, Grosveld F, Galjart N, de Laat W. CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus. Genes Dev. 2006;20(17):2349-54.
[21] Fedoriw AM, Stein P, Svoboda P, Schultz RM, Bartolomei MS. Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting. Science. 2004;303(5655):238-40.
[22] Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129(4):823-37.
[23] Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh YH, Yeo HC, Yeo ZX, Narang V, Govindarajan KR, Leong B, Shahab A, Ruan Y, Bourque G, Sung WK, Clarke ND, Wei CL, Ng HH. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell. 2008;133(6):1106-17.
[24] Kim TH, Abdullaev ZK, Smith AD, Ching KA, Loukinov DI, Green RD, Zhang MQ, Lobanenkov VV, Ren B. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell. 2007;128(6):1231-45.
[25] Whitington T, Perkins AC, Bailey TL. High-throughput chromatin information enables accurate tissue-specific prediction of transcription factor binding sites. Nucleic Acids Res. 2009;37(1):14-25.
[26] Rhee HS, Pugh BF. Comprehensive genome-wide protein-DNA interactions detected at single-nucleotide resolution. Cell. 2011;147(6):1408-19.
[27] Nakahashi H, Kwon KR, Resch W, Vian L, Dose M, Stavreva D, Hakim O, Pruett N, Nelson S, Yamane A, Qian J, Dubois W, Welsh S, Phair RD, Pugh BF, Lobanenkov V, Hager GL, Casellas R. A genome-wide map of CTCF multivalency redefines the CTCF code. Cell Rep. 2013;3(5):1678-89.
[28] Ziebarth JD, Bhattacharya A, Cui Y. CTCFBSDB 2.0: a database for CTCF-binding sites and genome organization. Nucleic Acids Res. 2013;41(Database issue):D188-94.
[29] Engel N, West AG, Felsenfeld G, Bartolomei MS. Antagonism between DNA hypermethylation and enhancer-blocking activity at the H19 DMD is uncovered by CpG mutations. Nat Genet. 2004;36(8):883-8.
[30] Renda M, Baglivo I, Burgess-Beusse B, Esposito S, Fattorusso R, Felsenfeld G, Pedone PV. Critical DNA binding interactions of the insulator protein CTCF: a small number of zinc fingers mediate strong binding, and a single finger-DNA interaction controls binding at imprinted loci. J Biol Chem. 2007;282(46):33336-45.
[31] Vostrov AA, Quitschke WW. The zinc finger protein CTCF binds to the APBbeta domain of the amyloid beta-protein precursor promoter. Evidence for a role in transcriptional activation. J Biol Chem. 1997;272(52):33353-9.
[32] Klug A. The discovery of zinc fingers and their development for practical applications in gene regulation and genome manipulation. Q Rev Biophys. 2010;43(1):1-21.
[33] MacPherson MJ, Sadowski PD. The CTCF insulator protein forms an unusual DNA structure. BMC Mol Biol. 2010;11:101.
[34] Handoko L, Xu H, Li G, Ngan CY, Chew E, Schnapp M, Lee CW, Ye C, Ping JL, Mulawadi F, Wong E, Sheng J, Zhang Y, Poh T, Chan CS, Kunarso G, Shahab A, Bourque G, Cacheux-Rataboul V, Sung WK, Ruan Y, Wei CL. CTCF-mediated functional chromatin interactome in pluripotent cells. Nat Genet. 2011;43(7):630-8.
[35] Bell AC, Felsenfeld G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature. 2000;405(6785):482-5.
[36] Filippova GN, Thienes CP, Penn BH, Cho DH, Hu YJ, Moore JM, Klesert TR, Lobanenkov VV, Tapscott SJ. CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nat Genet. 2001;28(4):335-43.
[37] Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature. 2000;405(6785):486-9.
[38] Kanduri C, Pant V, Loukinov D, Pugacheva E, Qi CF, Wolffe A, Ohlsson R, Lobanenkov VV. Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive. Curr Biol. 2000;10(14):853-6.
[39] Pant V, Mariano P, Kanduri C, Mattsson A, Lobanenkov V, Heuchel R, Ohlsson R. The nucleotides responsible for the direct physical contact between the chromatin insulator protein CTCF and the H19 imprinting control region manifest parent of origin-specific long-distance insulation and methylation-free domains. Genes Dev. 2003;17(5):586-90.
[40] Wang H, Maurano MT, Qu H, Varley KE, Gertz J, Pauli F, Lee K, Canfield T, Weaver M, Sandstrom R, Thurman RE, Kaul R, Myers RM, Stamatoyannopoulos JA. Widespread plasticity in CTCF occupancy linked to DNA methylation. Genome Res. 2012;22(9):1680-8.
[41] Yusufzai TM, Tagami H, Nakatani Y, Felsenfeld G. CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. Mol Cell. 2004;13(2):291-8.
[42] Ishihara K, Oshimura M, Nakao M. CTCF-dependent chromatin insulator is linked to epigenetic remodeling. Mol Cell. 2006;23(5):733-42.
[43] Chernukhin I, Shamsuddin S, Kang SY, Bergstr?m R, Kwon YW, Yu W, Whitehead J, Mukhopadhyay R, Docquier F, Farrar D, Morrison I, Vigneron M, Wu SY, Chiang CM, Loukinov D, Lobanenkov V, Ohlsson R, Klenova E. CTCF interacts with and recruits the largest subunit of RNA polymerase II to CTCF target sites genome-wide. Mol Cell Biol. 2007;27(5):1631-48.
[44] Donohoe ME, Zhang LF, Xu N, Shi Y, Lee JT. Identification of a Ctcf cofactor, Yy1, for the X chromosome binary switch. Mol Cell. 2007;25(1):43-56.
[45] Chernukhin IV, Shamsuddin S, Robinson AF, Carne AF, Paul A, El-Kady AI, Lobanenkov VV, Klenova EM. Physical and functional interaction between two pluripotent proteins, the Y-box DNA/RNA-binding factor, YB-1, and the multivalent zinc finger factor, CTCF. J Biol Chem. 2000;275(38):29915-21.
[46] De La Rosa-Vel?zquez IA, Rinc?n-Arano H, Ben?tez-Bribiesca L, Recillas-Targa F. Epigenetic regulation of the human retinoblastoma tumor suppressor gene promoter by CTCF. Cancer Res. 2007;67(6):2577-85.
[47] Lutz M, Burke LJ, Barreto G, Goeman F, Greb H, Arnold R, Schultheiss H, Brehm A, Kouzarides T, Lobanenkov V, Renkawitz R. Transcriptional repression by the insulator protein CTCF involves histone deacetylases. Nucleic Acids Res. 2000;28(8):1707-13.
[48] Guastafierro T, Cecchinelli B, Zampieri M, Reale A, Riggio G, Sthandier O, Zupi G, Calabrese L, Caiafa P. CCCTC-binding factor activates PARP-1 affecting DNA methylation machinery. J Biol Chem. 2008;283(32):21873-80.
[49] Yao H, Brick K, Evrard Y, Xiao T, Camerini-Otero RD, Felsenfeld G. Mediation of CTCF transcriptional insulation by DEAD-box RNA-binding protein p68 and steroid receptor RNA activator SRA. Genes Dev. 2010;24(22):2543-55.
[50] Zlatanova J, Caiafa P. CCCTC-binding factor: to loop or to bridge. Cell Mol Life Sci. 2009;66(10):1647-60.
[51] Hirano T. At the heart of the chromosome: SMC proteins in action. Nat Rev Mol Cell Biol. 2006;7(5):311-22.
[52] Ishiguro K, Watanabe Y. Chromosome cohesion in mitosis and meiosis. J Cell Sci. 2007;120(Pt 3):367-9.
[53] Peters JM, Tedeschi A, Schmitz J. The cohesin complex and its roles in chromosome biology. Genes Dev. 2008;22(22):3089-114.
[54] Haering CH, L?we J, Hochwagen A, Nasmyth K. Molecular architecture of SMC proteins and the yeast cohesin complex. Mol Cell. 2002;9(4):773-88.
[55] Degner SC, Verma-Gaur J, Wong TP, Bossen C, Iverson GM, Torkamani A, Vettermann C, Lin YC, Ju Z, Schulz D, Murre CS, Birshtein BK, Schork NJ, Schlissel MS, Riblet R, Murre C, Feeney AJ. CCCTC-binding factor (CTCF) and cohesin influence the genomic architecture of the Igh locus and antisense transcription in pro-B cells. Proc Natl Acad Sci U S A. 2011;108(23):9566-71.
[56] Hadjur S, Williams LM, Ryan NK, Cobb BS, Sexton T, Fraser P, Fisher AG, Merkenschlager M. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature. 2009;460(7253):410-3.
[57] Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA, van Berkum NL, Ebmeier CC, Goossens J, Rahl PB, Levine SS, Taatjes DJ, Dekker J, Young RA. Mediator and cohesin connect gene expression and chromatin architecture. Nature. 2010;467(7314):430-5.
[58] Parelho V, Hadjur S, Spivakov M, Leleu M, Sauer S, Gregson HC, Jarmuz A, Canzonetta C, Webster Z, Nesterova T, Cobb BS, Yokomori K, Dillon N, Aragon L, Fisher AG, Merkenschlager M. Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell. 2008;132(3):422-33.
[59] Rubio ED, Reiss DJ, Welcsh PL, Disteche CM, Filippova GN, Baliga NS, Aebersold R, Ranish JA, Krumm A. CTCF physically links cohesin to chromatin. Proc Natl Acad Sci U S A. 2008;105(24):8309-14.
[60] Wendt KS, Yoshida K, Itoh T, Bando M, Koch B, Schirghuber E, Tsutsumi S, Nagae G, Ishihara K, Mishiro T, Yahata K, Imamoto F, Aburatani H, Nakao M, Imamoto N, Maeshima K, Shirahige K, Peters JM. Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature. 2008;451(7180):796-801.
[61] Xiao T, Wallace J, Felsenfeld G. Specific sites in the C terminus of CTCF interact with the SA2 subunit of the cohesin complex and are required for cohesin-dependent insulation activity. Mol Cell Biol. 2011;31(11):2174-83.
[62] Herold M, Bartkuhn M, Renkawitz R. CTCF: insights into insulator function during development. Development. 2012;139(6):1045-57.
[63] Magdinier F, Yusufzai TM, Felsenfeld G. Both CTCF-dependent and -independent insulators are found between the mouse T cell receptor alpha and Dad1 genes. J Biol Chem. 2004;279(24):25381-9.
[64] Chambeyron S, Bickmore WA. Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription. Genes Dev. 2004;18(10):1119-30.
[65] Ferrai C, Xie SQ, Luraghi P, Munari D, Ramirez F, Branco MR, Pombo A, Crippa MP. Poised transcription factories prime silent uPA gene prior to activation. PLoS Biol. 2010;8(1):e1000270.
[66] Mahy NL, Perry PE, Bickmore WA. Gene density and transcription influence the localization of chromatin outside of chromosome territories detectable by FISH. J Cell Biol. 2002;159(5):753-63.
[67] Osborne CS, Chakalova L, Brown KE, Carter D, Horton A, Debrand E, Goyenechea B, Mitchell JA, Lopes S, Reik W, Fraser P. Active genes dynamically colocalize to shared sites of ongoing transcription. Nat Genet. 2004;36(10):1065-71.
[68] Wei Z, Huang D, Gao F, Chang WH, An W, Coetzee GA, Wang K, Lu W. Biological implications and regulatory mechanisms of long-range chromosomal interactions. J Biol Chem. 2013;288(31):22369-77.
[69] Bodnar JW. A domain model for eukaryotic DNA organization: a molecular basis for cell differentiation and chromosome evolution. J Theor Biol. 1988;132(4):479-507.
[70] Goldman MA. The chromatin domain as a unit of gene regulation. Bioessays. 1988;9(2-3):50-5.
[71] Anguita E, Johnson CA, Wood WG, Turner BM, Higgs DR. Identification of a conserved erythroid specific domain of histone acetylation across the alpha-globin gene cluster. Proc Natl Acad Sci U S A. 2001;98(21):12114-9.
[72] Krajewski WA, Becker PB. Reconstitution of hyperacetylated, DNase I-sensitive chromatin characterized by high conformational flexibility of nucleosomal DNA. Proc Natl Acad Sci U S A. 1998;95(4):1540-5.
[73] Forrester WC, Epner E, Driscoll MC, Enver T, Brice M, Papayannopoulou T, Groudine M. A deletion of the human beta-globin locus activation region causes a major alteration in chromatin structure and replication across the entire beta-globin locus. Genes Dev. 1990;4(10):1637-49.
[74] Grosveld F, van Assendelft GB, Greaves DR, Kollias G. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell. 1987;51(6):975-85.
[75] Razin SV, Farrell CM, Recillas-Targa F. Genomic domains and regulatory elements operating at the domain level. Int Rev Cytol. 2003;226:63-125.
[76] Felsenfeld G. Chromatin structure and the expression of globin-encoding genes. Gene. 1993;135(1-2):119-24.
[77] Hebbes TR, Clayton AL, Thorne AW, Crane-Robinson C. Core histone hyperacetylation co-maps with generalized DNase I sensitivity in the chicken beta-globin chromosomal domain. EMBO J. 1994;13(8):1823-30.
[78] Litt MD, Simpson M, Recillas-Targa F, Prioleau MN, Felsenfeld G. Transitions in histone acetylation reveal boundaries of three separately regulated neighboring loci. EMBO J. 2001;20(9):2224-35.
[79] Kurukuti S, Tiwari VK, Tavoosidana G, Pugacheva E, Murrell A, Zhao Z, Lobanenkov V, Reik W, Ohlsson R. CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2. Proc Natl Acad Sci U S A. 2006;103(28):10684-9.
[80] Palstra RJ, Tolhuis B, Splinter E, Nijmeijer R, Grosveld F, de Laat W. The beta-globin nuclear compartment in development and erythroid differentiation. Nat Genet. 2003;35(2):190-4.
[81] Ulianov SV, Gavrilov AA, Razin SV. Spatial organization of the chicken beta-globin gene domain in erythroid cells of embryonic and adult lineages. Epigenetics Chromatin. 2012;5(1):16.
[82] Wang L, Di LJ, Lv X, Zheng W, Xue Z, Guo ZC, Liu DP, Liang CC. Inter-MAR association contributes to transcriptionally active looping events in human beta-globin gene cluster. PLoS One. 2009;4(2):e4629.
[83] Yusufzai TM, Felsenfeld G. The 5'-HS4 chicken beta-globin insulator is a CTCF-dependent nuclear matrix-associated element. Proc Natl Acad Sci U S A. 2004;101(23):8620-4.
[84] Guo Y, Monahan K, Wu H, Gertz J, Varley KE, Li W, Myers RM, Maniatis T, Wu Q. CTCF/cohesin-mediated DNA looping is required for protocadherin ? promoter choice. Proc Natl Acad Sci U S A. 2012;109(51):21081-6.
[85] Mitchell JA, Fraser P. Transcription factories are nuclear subcompartments that remain in the absence of transcription. Genes Dev. 2008;22(1):20-5.
[86] Hu Q, Kwon YS, Nunez E, Cardamone MD, Hutt KR, Ohgi KA, Garcia-Bassets I, Rose DW, Glass CK, Rosenfeld MG, Fu XD. Enhancing nuclear receptor-induced transcription requires nuclear motor and LSD1-dependent gene networking in interchromatin granules. Proc Natl Acad Sci U S A. 2008;105(49):19199-204.
[87] Li G, Ruan X, Auerbach RK, Sandhu KS, Zheng M, Wang P, Poh HM, Goh Y, Lim J, Zhang J, Sim HS, Peh SQ, Mulawadi FH, Ong CT, Orlov YL, Hong S, Zhang Z, Landt S, Raha D, Euskirchen G, Wei CL, Ge W, Wang H, Davis C, Fisher-Aylor KI, Mortazavi A, Gerstein M, Gingeras T, Wold B, Sun Y, Fullwood MJ, Cheung E, Liu E, Sung WK, Snyder M, Ruan Y. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell. 2012;148(1-2):84-98.
[88] Patel B, Kang Y, Cui K, Litt M, Riberio MS, Deng C, Salz T, Casada S, Fu X, Qiu Y, Zhao K, Huang S. Aberrant TAL1 activation is mediated by an interchromosomal interaction in human T-cell acute lymphoblastic leukemia. Leukemia. 2014;28(2):349-61.
[89] West AG, Gaszner M, Felsenfeld G. Insulators: many functions, many mechanisms. Genes Dev. 2002;16(3):271-88.
[90] Wallace JA, Felsenfeld G. We gather together: insulators and genome organization. Curr Opin Genet Dev. 2007;17(5):400-7.
[91] Dunn KL, Zhao H, Davie JR. The insulator binding protein CTCF associates with the nuclear matrix. Exp Cell Res. 2003;288(1):218-23.
[92] Gohl D, Aoki T, Blanton J, Shanower G, Kappes G, Schedl P. Mechanism of chromosomal boundary action: roadblock, sink, or loop? Genetics. 2011;187(3):731-48.
[93] Chien R, Zeng W, Kawauchi S, Bender MA, Santos R, Gregson HC, Schmiesing JA, Newkirk DA, Kong X, Ball AR Jr, Calof AL, Lander AD, Groudine MT, Yokomori K. Cohesin mediates chromatin interactions that regulate mammalian ?-globin expression. J Biol Chem. 2011;286(20):17870-8.
[94] Bulger M, Bender MA, van Doorninck JH, Wertman B, Farrell CM, Felsenfeld G, Groudine M, Hardison R. Comparative structural and functional analysis of the olfactory receptor genes flanking the human and mouse beta-globin gene clusters. Proc Natl Acad Sci U S A. 2000;97(26):14560-5.
[95] Sch?beler D, Francastel C, Cimbora DM, Reik A, Martin DI, Groudine M. Nuclear localization and histone acetylation: a pathway for chromatin opening and transcriptional activation of the human beta-globin locus. Genes Dev. 2000;14(8):940-50.
[96] Xie X, Mikkelsen TS, Gnirke A, Lindblad-Toh K, Kellis M, Lander ES. Systematic discovery of regulatory motifs in conserved regions of the human genome, including thousands of CTCF insulator sites. Proc Natl Acad Sci U S A. 2007;104(17):7145-50.
[97] Recillas-Targa F, Bell AC, Felsenfeld G. Positional enhancer-blocking activity of the chicken beta-globin insulator in transiently transfected cells. Proc Natl Acad Sci U S A. 1999;96(25):14354-9.
[98] Akopov SB, Ruda VM, Batrak VV, Vetchinova AS, Chernov IP, Nikolaev LG, Bode J, Sverdlov ED. Identification, genome mapping, and CTCF binding of potential insulators within the FXYD5-COX7A1 locus of human chromosome 19q13.12. Mamm Genome. 2006;17(10):1042-9.
[99] Didych DA, Kotova ES, Akopov SB, Nikolaev LG, Sverdlov ED. DNA fragments binding CTCF in vitro and in vivo are capable of blocking enhancer activity. BMC Res Notes. 2012;5:178.
[100] Vetchinova AS, Akopov SB, Chernov IP, Nikolaev LG, Sverdlov ED. Two-dimensional electrophoretic mobility shift assay: identification and mapping of transcription factor CTCF target sequences within an FXYD5-COX7A1 region of human chromosome 19. Anal Biochem. 2006;354(1):85-93.
[101] Zhao H, Dean A. An insulator blocks spreading of histone acetylation and interferes with RNA polymerase II transfer between an enhancer and gene. Nucleic Acids Res. 2004;32(16):4903-19.
[102] Chung JH, Bell AC, Felsenfeld G. Characterization of the chicken beta-globin insulator. Proc Natl Acad Sci U S A. 1997;94(2):575-80.
[103] Harmston N, Lenhard B. Chromatin and epigenetic features of long-range gene regulation. Nucleic Acids Res. 2013;41(15):7185-99.
[104] Kulaeva OI, Nizovtseva EV, Polikanov YS, Ulianov SV, Studitsky VM. Distant activation of transcription: mechanisms of enhancer action. Mol Cell Biol. 2012;32(24):4892-7.
[105] Simonis M, Kooren J, de Laat W. An evaluation of 3C-based methods to capture DNA interactions. Nat Methods. 2007;4(11):895-901.
[106] Tolhuis B, Palstra RJ, Splinter E, Grosveld F, de Laat W. Looping and interaction between hypersensitive sites in the active beta-globin locus. Mol Cell. 2002;10(6):1453-65.
[107] Tsytsykova AV, Rajsbaum R, Falvo JV, Ligeiro F, Neely SR, Goldfeld AE. Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers. Proc Natl Acad Sci U S A. 2007;104(43):16850-5.
[108] Krivega I, Dean A. Enhancer and promoter interactions-long distance calls. Curr Opin Genet Dev. 2012;22(2):79-85.
[109] Geyer PK. The role of insulator elements in defining domains of gene expression. Curr Opin Genet Dev. 1997;7(2):242-8.
[110] Pikaart MJ, Recillas-Targa F, Felsenfeld G. Loss of transcriptional activity of a transgene is accompanied by DNA methylation and histone deacetylation and is prevented by insulators. Genes Dev. 1998;12(18):2852-62.
[111] Cuddapah S, Jothi R, Schones DE, Roh TY, Cui K, Zhao K. Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. Genome Res. 2009;19(1):24-32.
[112] Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, Hu M, Liu JS, Ren B. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485(7398):376-80.
[113] Gomes NP, Espinosa JM. Gene-specific repression of the p53 target gene PUMA via intragenic CTCF-Cohesin binding. Genes Dev. 2010;24(10):1022-34.
[114] Vostrov AA, Taheny MJ, Quitschke WW. A region to the N-terminal side of the CTCF zinc finger domain is essential for activating transcription from the amyloid precursor protein promoter. J Biol Chem. 2002;277(2):1619-27.
[115] Ribich S, Tasic B, Maniatis T. Identification of long-range regulatory elements in the protocadherin-alpha gene cluster. Proc Natl Acad Sci U S A. 2006;103(52):19719-24.
[116] Kehayova P, Monahan K, Chen W, Maniatis T. Regulatory elements required for the activation and repression of the protocadherin-alpha gene cluster. Proc Natl Acad Sci U S A. 2011;108(41):17195-200.
[117] Monahan K, Rudnick ND, Kehayova PD, Pauli F, Newberry KM, Myers RM, Maniatis T. Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of protocadherin-? gene expression. Proc Natl Acad Sci U S A. 2012;109(23):9125-30.
[118] Lutz M, Burke LJ, LeFevre P, Myers FA, Thorne AW, Crane-Robinson C, Bonifer C, Filippova GN, Lobanenkov V, Renkawitz R. Thyroid hormone-regulated enhancer blocking: cooperation of CTCF and thyroid hormone receptor. EMBO J. 2003;22(7):1579-87.
[119] Lai AY, Fatemi M, Dhasarathy A, Malone C, Sobol SE, Geigerman C, Jaye DL, Mav D, Shah R, Li L, Wade PA. DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas. J Exp Med. 2010;207(9):1939-50.
[120] Renaud S, Loukinov D, Bosman FT, Lobanenkov V, Benhattar J. CTCF binds the proximal exonic region of hTERT and inhibits its transcription. Nucleic Acids Res. 2005;33(21):6850-60.
[121] Renaud S, Loukinov D, Abdullaev Z, Guilleret I, Bosman FT, Lobanenkov V, Benhattar J. Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene. Nucleic Acids Res. 2007;35(4):1245-56.
[122] M?ndez-Catal? CF, Gretton S, Vostrov A, Pugacheva E, Farrar D, Ito Y, Docquier F, Kita GX, Murrell A, Lobanenkov V, Klenova E. A novel mechanism for CTCF in the epigenetic regulation of Bax in breast cancer cells. Neoplasia. 2013;15(8):898-912.
[123] Rayess H, Wang MB, Srivatsan ES. Cellular senescence and tumor suppressor gene p16. Int J Cancer. 2012;130(8):1715-25.
[124] Huang K, Jia J, Wu C, Yao M, Li M, Jin J, Jiang C, Cai Y, Pei D, Pan G, Yao H. Ribosomal RNA gene transcription mediated by the master genome regulator protein CCCTC-binding factor (CTCF) is negatively regulated by the condensin complex. J Biol Chem. 2013;288(36):26067-77.
[125] Kanduri C, Holmgren C, Pilartz M, Franklin G, Kanduri M, Liu L, Ginjala V, Uller?s E, Mattsson R, Ohlsson R. The 5' flank of mouse H19 in an unusual chromatin conformation unidirectionally blocks enhancer-promoter communication. Curr Biol. 2000;10(8):449-57.
[126] Gabory A, Jammes H, Dandolo L. The H19 locus: role of an imprinted non-coding RNA in growth and development. Bioessays. 2010;32(6):473-80.
[127] Leighton PA, Saam JR, Ingram RS, Stewart CL, Tilghman SM. An enhancer deletion affects both H19 and Igf2 expression. Genes Dev. 1995;9(17):2079-89.
[128] Lewis A, Murrell A. Genomic imprinting: CTCF protects the boundaries. Curr Biol. 2004;14(7):R284-6.
[129] Schoenherr CJ, Levorse JM, Tilghman SM. CTCF maintains differential methylation at the Igf2/H19 locus. Nat Genet. 2003;33(1):66-9.
[130] Szab? PE, Tang SH, Silva FJ, Tsark WM, Mann JR. Role of CTCF binding sites in the Igf2/H19 imprinting control region. Mol Cell Biol. 2004;24(11):4791-800.
[131] Gao ZH, Suppola S, Liu J, Heikkil? P, J?nne J, Voutilainen R. Association of H19 promoter methylation with the expression of H19 and IGF-II genes in adrenocortical tumors. J Clin Endocrinol Metab. 2002;87(3):1170-6.
[132] Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT. CTCF, a candidate trans-acting factor for X-inactivation choice. Science. 2002;295(5553):345-7.
[133] Lee JT. Lessons from X-chromosome inactivation: long ncRNA as guides and tethers to the epigenome. Genes Dev. 2009;23(16):1831-42.
[134] Avner P, Heard E. X-chromosome inactivation: counting, choice and initiation. Nat Rev Genet. 2001;2(1):59-67.
[135] Clerc P, Avner P. Random X-chromosome inactivation: skewing lessons for mice and men. Curr Opin Genet Dev. 2006;16(3):246-53.
[136] Erwin JA, Lee JT. New twists in X-chromosome inactivation. Curr Opin Cell Biol. 2008;20(3):349-55.
[137] Bacher CP, Guggiari M, Brors B, Augui S, Clerc P, Avner P, Eils R, Heard E. Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation. Nat Cell Biol. 2006;8(3):293-9.
[138] Xu N, Tsai CL, Lee JT. Transient homologous chromosome pairing marks the onset of X inactivation. Science. 2006;311(5764):1149-52.
[139] Xu N, Donohoe ME, Silva SS, Lee JT. Evidence that homologous X-chromosome pairing requires transcription and Ctcf protein. Nat Genet. 2007;39(11):1390-6.
[140] Nicodemi M, Panning B, Prisco A. A thermodynamic switch for chromosome colocalization. Genetics. 2008;179(1):717-21.
[141] Nicodemi M, Prisco A. Self-assembly and DNA binding of the blocking factor in x chromosome inactivation. PLoS Comput Biol. 2007;3(11):e210.
[142] Nicodemi M, Prisco A. Symmetry-breaking model for X-chromosome inactivation. Phys Rev Lett. 2007;98(10):108104.
[143] Sun BK, Deaton AM, Lee JT. A transient heterochromatic state in Xist preempts X inactivation choice without RNA stabilization. Mol Cell. 2006;21(5):617-28.
[144] Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science. 2008;322(5902):750-6.
[145] Hoki Y, Kimura N, Kanbayashi M, Amakawa Y, Ohhata T, Sasaki H, Sado T. A proximal conserved repeat in the Xist gene is essential as a genomic element for X-inactivation in mouse. Development. 2009;136(1):139-46.
[146] Wutz A, Rasmussen TP, Jaenisch R. Chromosomal silencing and localization are mediated by different domains of Xist RNA. Nat Genet. 2002;30(2):167-74.
[147] Pugacheva EM, Tiwari VK, Abdullaev Z, Vostrov AA, Flanagan PT, Quitschke WW, Loukinov DI, Ohlsson R, Lobanenkov VV. Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation. Hum Mol Genet. 2005;14(7):953-65.
[148] Filippova GN, Cheng MK, Moore JM, Truong JP, Hu YJ, Nguyen DK, Tsuchiya KD, Disteche CM. Boundaries between chromosomal domains of X inactivation and escape bind CTCF and lack CpG methylation during early development. Dev Cell. 2005;8(1):31-42.
[149] Shukla S, Kavak E, Gregory M, Imashimizu M, Shutinoski B, Kashlev M, Oberdoerffer P, Sandberg R, Oberdoerffer S. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature. 2011;479(7371):74-9.
[150] Wada Y, Ohta Y, Xu M, Tsutsumi S, Minami T, Inoue K, Komura D, Kitakami J, Oshida N, Papantonis A, Izumi A, Kobayashi M, Meguro H, Kanki Y, Mimura I, Yamamoto K, Mataki C, Hamakubo T, Shirahige K, Aburatani H, Kimura H, Kodama T, Cook PR, Ihara S. A wave of nascent transcription on activated human genes. Proc Natl Acad Sci U S A. 2009;106(43):18357-61.
[151] Kornblihtt AR. CTCF: from insulators to alternative splicing regulation. Cell Res. 2012;22(3):450-2.